1. Field of the Invention
The present invention relates to the field of treatments for cancer tumors. More particularly, the present invention relates to interstitial therapy for brain tumors by delivering a compound of the 1,2,4-benzotriazine oxides family contained in a biodegradable polymer slowly released to the site of the tumor.
2. Reported Developments
Glioblastoma multiforme (GBM) patient management remains a formidable task. Radiation therapy improves median survival, and the addition of chemotherapy with nitrosources adds a modest gain for selected patients (See, for example: Kornblith, P. L. et al, Chemotherapy for malignant gliomas. J. Neurosurg. 68: 1-17 (1988); and Walker, M. D. et al, Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery, N. Eng. J. Med., 303: 1323-1329 (1980)). The benefit of radiotherapy, however, is limited by several factors. Although intrinsic radioresistance and rapid cellular proliferation may contribute to therapeutic inefficacy, dose escalation has not yet yielded superior results and is limited by the radiation tolerance of normal brain as reported by Solazar, O. M. et at, High dose radiation therapy in the treatment of malignant gliomas: final report, Int. J. Radial. Oncol. Biol. Phys., 3: 1733-1740 (1979). Hypoxic radioresistance has been demonstrated in several tumor types, including GBM, and oxygen measurements document regional hypoxia in a high percentage of patients with GBM, as reported by, inter alia: Gatenby, R. A. et al, Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int. J. Radial. Oncol. Biol. Phys. 14: 831-838; (1988); Kayama, T. et al, Intratumoral oxygen pressure in malignant brain tumors, J. Neurosurg., 74: 55-59 (1991); Rampling, R. et al, Direct measurement of pO2 distribution and bioreductive enzymes in human malignant brain tumors, Int. J. Radiat. Oncol. Biol. Phys. 29: 427-431 (1994); and Valk, P. E. et at, Hypoxia in human gliomas: demonstration by PET with fluorine-18-fluoromisonidazole, J. Nucl. Med. 33: 2133-2137 (1992)). A treatment that kills radioresistant hypoxic tumor cells should improve the efficacy of radiation therapy.
When given as multiple injections in conjunction with fractionated irradiation, tirapazamine (SR-4233), a bioreductive agent that preferentially kills hypoxic dells, increases tumor cell kill while sparing normal tissue in mouse SCCVII and other tumors as reported by: Brown, J. M. et al, Potentiation by the hypoxic cytotoxin SR 4233 of cell killing produced by fractionated irradiation of mouse tumors, Cancer Res. 50: 7745-7749 (1990) and Brown, J. M. et al, SR 4233: a tumor specific radiosensitizer active in fractionated radiation regimens, Radiother. and Oncol., 20: 151-156 (1991). Brown has considered that tumor hypoxia may actually be of a therapeutic advantage when combining a hypoxic cytotoxin such as tirapazamine with fractionareal irradiation: Brown, J. M. et al, Tumor hypoxia: the picture has changed in the 1990s., Int. J. Radiat. Biol., 65: 95-102 (1994); and Brown, J. M. et al, Therapeutic advantage of hypoxic cells in tumors: a theoretical study, J. Nat. Can. Inst., 83: 178-185 (1991).
We have now discovered that 1, 2, 4-benzotriazine oxides contained in synthetic biodegradable polymer such as polyanhydride polymer, which allows sustained, controlled release, may be used to maximize exposure directly to the cancer tumors and target local hypoxic regions while avoiding systemic toxicity. The 1, 2, 4-benzotriazine compounds contained in said polymer is delivered to the site of the tumor by surgical implantation.
Implants made of biodegradable polymers to deliver drugs to the brain have been reported in the art, for example: Brem, H., Polymers to treat brain tumors, Biomaterials, 11: 699-710 (1990); Brem, H. et al, Biodegradable polymers for controlled delivery of chemotherapy with and without radiation therapy in the monkey brain, J. Neurosurg., 80: 283-290 (1994); and Tamargo, R. J. et at, Interstitial chemotherapy of the 9L gliosarcoma: controlled release polymers for drug delivery in the brain, Cancer Res. 53: 329-333 (1993).
None of these or other references that we are aware of pertain to a method of treating cancer tumors by implantation of a biodegradable polymer containing 1,2,4-benzotriazine oxides.
1,2,4-Benzotriazine oxides are known compounds. U.S. Pat. No. 3,980,779 discloses 3-amino-1,2,4-benzotriazine-1,4-di-oxide compositions having the formula ##STR1## wherein
one of R and R.sup.1 is hydrogen, halogen, lower alkyl, halo (lower alkyl), lower alkoxy, carbamoyl, sulfonamido, carboxy or carbo (lower alkoxy) and the other of R and R.sup.1 is halogeno, lower alkyl, halo (lower alkyl), lower alkoxy, carbamoyl, sulfonamido, carboxy or carbo (lower alkoxy),
as antimicrobial composition used to promote livestock growth.
U.S. Pat. No. 5,175,287 issued Dec. 29, 1992 discloses the use of 1,2,4-benzotriazine oxides in conjunction with radiation for treatment of tumors. The 1,2,4-benzotriazine oxides sensitize the tumor cells to radiation and make them more amenable to this treatment modality.
Holden et al (1992) "Enhancement of Alkylating Agent Activity by SR-4233 in the FSalIC Murine Fibrosarcoma" JNCI 84: 187-193 discloses the use of SR-4233, namely 3-amino-1,2,4-benzotriazine-1,4-dioxide, also known and hereinafter sometimes referred to as tirapazamine, in combination with an antitumor alkylating agent. The four antitumor alkylating agents, cisplatin, cyclophosphamide, carmustine and melphalan, were each tested to examine the ability of tirapazamine to overcome the resistance of hypoxic tumor cells to antitumor alkylating agents. Tirapazamine was tested alone and in combination with varying amounts of each of the antitumor alkylating agents. When SR-4233 was administered just before single-dose treatment with cyclophosphamide, carmustine or melphalan marked dose enhancement leading to synergistic cytotoxic effects on tumor cells was observed.
International Application No. PCT/US89/01037 discloses 1,2,4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents. Other related patents include: U.S. Pat. Nos. 3,868,372 and 4,001,410 which disclose the preparation of 1,2,4-benzotriazine oxides; and U.S. Pat. Nos. 3,991,189 and 3,957,799 which disclose derivatives of 1,2,4-benzotriazine oxides.